Bladdercancer(BC)isthe4thmostcommoncancerinmenandthe11thmostcommoninwomen.BC has the highest lifetime per-patient treatment cost of all cancers, mainly because of its high recurrence rate. Also, regular invasive cystoscopy and the subsequent surgical treatment of recurrences impair patient quality of life and cause significant morbidity. Therefore, there is a clear clinical need for novel technologies to effectively treat BC, ultimately reducing tumor recurrences, treatment costs, number of radical cystectomies, and mortality. A promising therapeutic platform for cancer is offered by gold nanoparticles (GNP). Taking advantage of gold?s high biocompatibility, GNP can be injected intravenously and accumulate preferentially in cancer cells due to the enhanced permeability and retention effect. Among GNP platforms, gold nanostars (GNS) have great therapeutic potential due to the unique star-shaped geometry that dramatically enhances lightabsorptionandeffectiveconversionintoheatduetotheplasmoniceffect.Thisphotothermalprocesscan beexploitedtospecificallyablatetumorsand,importantly,toamplifytheanti-tumorimmuneresponsefollowing thehighlyimmunogenicthermaldeathofcancercells.Relatedly,manycancersexploitimmunecheckpoints? such as the interaction between programmed cell death 1 (PD-1) and its ligand (PD-L1) ? to evade the anti- cancerimmuneresponse.Recentimmunotherapiesdisablingthisimmuneresistancemechanismhaveshown encouragingclinicalresults,areFDAapprovedinBC,butdonotofferapermanentcureformostpatients. We thus propose to develop the GNS technology for use in SYnergistic iMmuno PHOtothermal NanotherapY (SYMPHONY), a novel therapy that integrates nanotechnology, biophotonics, and immunotherapy. The central hypothesis of this proposal is that combining GNS-mediated photothermal nanotherapy with PD-1/PD-L1 immune checkpoint blockade will result in dramatic therapeutic synergism to treat cancer metastasis. The rationale for this hypothesis is that photothermal therapy not only reduces tumor burden by direct heat-based ablation, but also causes intense immune responses that can be amplified with PD-1/PD-L1immunecheckpointblockade.Thespecificaimsare:(1)Fabricateandmodulateopticalproperties of next-generation plasmonics GNS to maximize photothermal therapy of deep tumors;? (2) Coat and functionalize GNS to safely improve in vivo BC targeting;? and (3) Evaluate effectiveness of SYMPHONY therapy for treating BC in murine models. The results of our research proposal intends to prove that nanoparticle therapy and immunotherapy can be synergistically combined to produce an antitumor systemic responsefarsuperiortoeithersingletherapyalone.WewillalsoprovethatSYMPHONYtriggersanextremely potent systemic response that cures both primary and distant lesions, producing a ?vaccine? effect to prevent future BC recurrences. The proposed work will set the stage for SYMPHONY?s rapid future clinical translation toimprovelifequalityandreducemortalityofBCpatients.